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Molecular and Cellular Biology, August 1999, p. 5800-5810, Vol. 19, No. 8
Department of Molecular Genetics, University
of Illinois at Chicago, Chicago, Illinois 60607
Received 9 March 1999/Returned for modification 26 April
1999/Accepted 13 May 1999
Growth factors signaling through the phosphoinositide 3-kinase/Akt
pathway promote cell survival. The mechanism by which the serine/threonine kinase Akt prevents cell death remains unclear. We
have previously shown that Akt inhibits the activity of DEVD-targeted caspases without changing the steady-state levels of Bcl-2 and Bcl-xL. Here we show that Akt inhibits apoptosis and the
processing of procaspases to their active forms by delaying
mitochondrial changes in a caspase-independent manner. Akt activation
is sufficient to inhibit the release of cytochrome c from
mitochondria and the alterations in the inner mitochondrial membrane
potential. However, Akt cannot inhibit apoptosis induced by
microinjection of cytochrome c. We also demonstrated that
Akt inhibits apoptosis and cytochrome c release induced by
several proapoptotic Bcl-2 family members. Taken together, our results
show that Akt promotes cell survival by intervening in the apoptosis
cascade before cytochrome c release and caspase activation
via a mechanism that is distinct from Bad phosphorylation.
Apoptosis is an essential process
for the development and tissue homeostasis of most multicellular
organisms. Deregulation of apoptosis has been implicated in the
pathogenesis of many disease states, including neurodegenerative
disorders and cancer (37). One mechanism by which apoptosis
is regulated is through the availability of mediators of survival
signals, such as certain growth factors and cytokines and cell-matrix
contact (32, 33).
The activation of growth factor receptors leads to multiple
intracellular effects, including alterations in gene expression, protein synthesis, mitogenesis, cytoskeletal rearrangements,
differentiation, and cell survival. The pathway leading to the
activation of phosphoinositide 3-kinase (PI 3-kinase) and its
downstream effector the serine/threonine kinase Akt (also called
protein kinase B [PKB]) by growth factor receptors has emerged as the
major mechanism by which growth factors promote cell survival (reviewed
in reference 28). Upon activation, PI 3-kinase
phosphorylates membrane phosphoinositides at the D-3 position. These
phospholipids act as second messengers that mediate the diverse
cellular functions of PI 3-kinase (13). One function of
these second messengers is the activation of Akt. The amino terminus of
Akt contains a pleckstrin homology domain that is thought to directly
bind the phospholipid products of PI 3-kinase. This binding recruits
Akt to the membrane and induces a conformational change that allows the
phosphorylation of Akt by the phosphoinositide-dependent kinases I
(PDKI) and PDKII at residues Thr308 and Ser473, respectively. Phosphorylation of Akt results in full activation of Akt kinase activity and the subsequent regulation of multiple cellular processes, including the transmission of growth factor-dependent survival signal
(reviewed in references 7 and
28). Recent genetic studies in Drosophila
melanogaster have corroborated these results and have suggested an
important in vivo role for Akt in the regulation of apoptosis (3,
36).
Although Akt promotes cell survival in a variety of cell types and
blocks apoptosis induced by diverse apoptotic stimuli, the step at
which Akt abrogates the apoptotic cascade is not known. Because Akt is
blocking apoptosis both in mammalian cells and in
Drosophila, it is likely that the mechanism by which Akt
intervenes in the apoptotic cascade is evolutionarily conserved.
The apoptotic cascade in mammalian cells is a multistep process
(reviewed in reference 15). In most cases, the
apoptotic cascade is initiated by loss of integrity of the outer
mitochondrial membrane accompanied by release of cytochrome
c. Following mitochondrial release, cytochrome c
is thought to bind and induce a conformational change in the apoptotic
protease activating factor (Apaf-I) that results in the cleavage and
activation of caspase-9 and a subsequent activation of a caspase
cascade that executes the cell death (reviewed in reference
38). However, the mechanism of cytochrome
c translocation from mitochondria into the cytosol and the
regulation of this translocation remained unclear.
The critical regulators of the apoptosis cascade are the Bcl-2 family
members. These family members include antiapoptotic proteins such as
Bcl-2 and Bcl-xL and proapoptotic members such as Bad, Bid,
and Bik (the BH3 subfamily) and Bax, and Bak (the Bax subfamily)
(reviewed in references 1 and
23). Many members of this family, such as Bcl-2 and
Bcl-xL, are predominantly localized to the outer membrane
of mitochondria, while others interact with mitochondria indirectly.
For example, the proapoptotic protein Bad does not contain a
mitochondrial targeting sequence but rather localizes to mitochondria,
in a phosphorylation-dependent manner, by heterodimerization with other
Bcl-2 family members (42, 44, 47). The mechanism by which
the Bcl-2 family members regulate cell death remains unclear but may
involve regulation of mitochondrial integrity (23). Bcl-2
family members may function as ion channels that regulate the osmotic
balance of mitochondria and the release of apoptogenic molecules from
mitochondria such as cytochrome c. Alternatively,
Bcl-2/Bcl-xL may function by binding and sequestering Apaf-I from interacting with caspase-9, thus preventing
Apaf-I-caspase-9 complex (apoptosome) formation and subsequent caspase
activation (reviewed in reference 15).
Elucidation of the mechanism by which Akt intervenes in the apoptotic
cascade is important not only for determining growth factor-mediated
cell survival but also for understanding the genesis of a wide range of
human cancers. This is in light of the observation that the PTEN
phosphatase tumor suppressor implicated in a wide range of human
cancers is a negative regulator of Akt (16, 27, 35, 43).
It was suggested that Akt inhibits apoptosis, at least in part, by
phosphorylating and inactivating the proapoptotic Bcl-2 family member,
Bad (8, 31). Here we provide evidence for a more general
mechanism by which Akt inhibits apoptosis that is not dependent on Bad
phosphorylation. We show that Akt promotes cell survival by maintaining
mitochondrial integrity and by inhibiting the release of cytochrome
c and alterations in mitochondrial membrane potential
induced by multiple apoptotic stimuli, in a caspase-independent manner.
Retroviral vectors.
The puromycin resistance gene of
pBabePuro was replaced with the enhanced green fluorescence protein
(eGFP) gene to construct pBabe(eGFP) (10). pSSFV Bad and
pSSFV Bad112/136 (gift from Stanley Korsmeyer) were digested with
EcoRI, and Bad coding sequences were inserted into the
EcoRI site of pBabe(eGFP). pSSFV murine Bax (gift from Craig
Thompson, University of Chicago) was digested with EcoRI,
and Bax was inserted into the EcoRI site of pBabe(eGFP). pCDNA3 HA-Bak and HA-Bik (provided by G. Chinnandurai, St. Louis University, St. Louis, Mo.) were digested with HindIII
and EcoRI and inserted into the BamHI and
EcoRI sites of pBabe(eGFP).
Cell culture and retrovirus production.
Cell culture and
quantitation of apoptosis by 4',6-diamidino-2-phenylindole (DAPI)
staining were performed as previously described (20).
For production of high-titer retroviruses expressing proapoptotic proteins, Phoenix ecotropic packaging cells were plated at
approximately 50 to 75% confluency in 15-cm-diameter tissue culture
plates and transfected by a modified calcium phosphate method. After 2 days, viral supernatant was collected and passed through a
0.22-mm-pore-size filter. Virus was added to cells in the presence of
Polybrene (8 µg/ml). Infected cells were visualized under an inverted
fluorescence microscope. Infected populations exhibiting between 85 and
95% green cells were used as polyclonal cell line for further experimentation.
Antibodies.
Bad was detected with a hamster monoclonal
anti-Bad antibody (product no. 13361S, PharMingen, La Jolla, Calif.)
used at a concentration of 1 µg/ml. Cytochrome c and
cytochrome c oxidase (COX) subunit IV were detected with
anti-cytochrome c clone 7H8.2C12 (1 µg/ml; PharMingen) and
anti-COX clone 20E8-C12 (1 µg/ml; Molecular Probes), respectively.
Biotinylated proteins were detected with horseradish
peroxidase-conjugated strepavidin (Zymed, San Francisco, Calif.) used
at a concentration of 1 µg/ml.
Cytochrome c immunostaining.
Rat1a cells were
plated at a density of 125,000 cells per 3-cm-diameter dish on glass
coverslips, fixed in phosphate-buffered saline (PBS) containing 4%
formaldehyde and 0.2% saponin, and then stained with Hoechst 33258 (1 µg/ml) for 20 min. The fixed cells were incubated in blocking buffer
(PBS containing 10% fetal calf serum [FCS] and 0.2% Triton X-100)
for 30 min and then for additional 30 min in PBS containing 0.2%
saponin, 2% bovine serum albumin (BSA), and 1 µg of anti-cytochrome
c antibody (clone 6H2.B4; PharMingen) per ml. Cells were
then washed three times in blocking buffer and incubated for 30 min in
PBS containing 2% BSA, 0.2% saponin, and 1 µg of
tetramethylrhodamine isothiocyanate-conjugated anti-mouse antibody
(Jackson ImmunoResearch, West Grove, Pa.) per ml. Cells were then
rinsed three times in blocking buffer, and coverslips were mounted onto slides.
Microinjection.
Cells were microinjected on a Leica DMIRB
inverted microscope using an Eppendorf (Madison, Wis.) micromanipulator
(5171) and Transjector (5246) microinjection system. Injection
needles (femtotips) were purchased from Eppendorf (product no. 5242 942.008). Rat1a cells were plated on glass coverslips at a density of
125,000 cells per 3-cm-diameter dish. Cells were injected (pressure,
100 hPa; time, 0.3 s) with a buffer containing 50 mM HEPES (pH
7.5), 50 mM NaCl, 0.2% Texas red (Mr, 10,000;
lysine fixable; (Molecular Probes), and either BSA (1 mg/ml;
FisherBiotech BP1600-100) or cytochrome c (1 mg/ml; Sigma
C7752). Following microinjection, coverslips were fixed for 3 min with
PBS containing 4% formaldehyde and the stained with Hoechst (1 µg/ml).
Subcellular fractionation.
Cells were scraped into 1 ml of
Mito buffer (250 mM sucrose, 20 mM HEPES, 10 mM KCl, 1.5 mM
MgCl2, 1 mM EDTA, 1 mM EGTA, 1 mM dithiothreitol, 10 µM
phenylmethylsulfonyl fluoride, 1× complete protease inhibitors
[product no. 1697498, Boehringer, Mannheim, Germany]). Cells were
then mechanically lysed at 4°C with 40 strokes of a cell homogenizer
(outer diameter, 0.1575 in.; inner diameter, 0.1560 in.). The cell
lysate was then spun at 1,000 × g for 10 min, and the
supernatant was further spun at 13,000 × g for an additional 20 min. This pellet was resuspended in 100 µl of Laemmli buffer and termed the mitochondrial pellet. The supernatant was incubated on ice with 20% trichloroacetic acid to precipitate cytochrome c. After 30 min, the supernatant was spun at
13,000 × g for 20 min; the pellet was then rinsed in 1 ml of diethyl ether on ice and respun at 13,000 × g
for 10 min. The diethyl ether was removed, and pellet was allowed to
dry on ice. The pellet was then resuspended in 70 µl of Laemmli
buffer and termed the supernatant.
DiOC6 labeling and FACS analysis.
Cells were
loaded with 50 nM 3',3'-dihexyloxacarbo-cyanine iodide
(DiOC6) at 37°C for 10 min. Floating cells were
collected, and attached cells were trypsinized and resuspended in PBS.
Cells were spun at 3,000 × g, and fractions were
pooled and rinsed in PBS. Cells were resuspended in 1 ml of ice-cold
PBS and subjected to fluorescence-activated cell sorting (FACS) analysis.
Akt inhibits UV light-mediated cell death and caspase activation in
Rat1a cells.
To further understand the mechanism by which Akt
mediates cell survival, we examined the ability of Akt to inhibit UV
light-induced cell death. Rat1a cells were placed in Dulbecco modified
Eagle medium (DMEM) containing no serum and then irradiated with UV light (50 Jo/m2). The percentage of apoptotic cells was
assessed 5 h following UV irradiation by staining with DAPI as
previously described (20). Fragmented and condensed nuclei
were scored as apoptotic. We observed a marked acceleration of
apoptosis following UV irradiation of Rat1a cells (Fig.
1A; P < 0.005). When
10% FCS was added to the cells, immediately after irradiation, there
was a significant attenuation of this cell death (P < 0.005). Preincubation of Rat1a cells with the PI 3-kinase
inhibitor wortmannin was sufficient to block the survival signal
generated by FCS (Fig. 1A). These results implicate PI 3-kinase in
transmitting the FCS-generated survival signal and are in agreement
with previous results demonstrating that PI 3-kinase can transmit an
antiapoptotic signal (19-21, 46).
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Akt/Protein Kinase B Inhibits Cell Death by
Preventing the Release of Cytochrome c from
Mitochondria
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
RESULTS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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FIG. 1.
Akt inhibits UV-mediated nuclei fragmentation, caspase
activation, and apoptosis in Rat1a cells. (A) Percentage of apoptotic
cells scored by DAPI staining of Rat1a (columns 1 to 4) and
Rat1a/MyrAkt (columns 5 and 6) cells. Cells were either mock treated or
treated with 200 nM wortmannin for 30 min (columns 4 and 6). Cells were
then irradiated with UVC light (260 nm) at a dose of 50 Joules/m2 (lanes 2 to 6). Medium containing either 0% FCS
(columns 1, 2, and 5 to 7) or 10% FCS (columns 3 and 4) was then
added. After an additional 4.5 h, cells were DAPI stained and
scored for nuclear condensation. Averages (± standard error) of at
least 300 cells from three independent experiments are shown. (B) Akt
inhibits the activation of at least two caspases during UV-mediated
apoptosis. Rat1a (lanes 1 to 3) and Rat1a/MyrAkt (lanes 4 and 5) cells
were deprived of serum for 2 h and irradiated with 50 J of
UVC light. The medium was then changed to DMEM with 0% FCS (lanes 2, 4, and 5) or 10% FCS (lanes 1 and 3). After an additional 5 h,
extracts were made and labeled with the biotin-conjugated YVAD-AMK
(Calbiochem, La Jolla, Calif.). Extracts were subjected to sodium
dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) on a 12%
gel, and the Western blot was incubated with horseradish
peroxidase-conjugated streptavidin (1 µg/ml).
Akt inhibits the release of cytochrome c from mitochondria following UV irradiation. The major mechanism of processing and activation of procaspases in mammalian cells is mediated by the Ced-4 homologue Apaf-I. Apaf-I is activated by binding to cytochrome c which is released from mitochondria in the early stage of apoptosis (reviewed in reference 15). We therefore examined whether Akt is capable of regulating the release of cytochrome c from mitochondria. Immunofluorescence staining of Rat1a cells with an anti-cytochrome c antibody gave a punctate staining pattern characteristic of mitochondrial localization (Fig. 2A, panel I). The mitochondrial dyes DiOC6 and MitoTracker-CMXRos gave indistinguishable patterns of fluorescence (see below), suggesting that the cytochrome c antibody did indeed recognize cytochrome c within mitochondria. Treatment of Rat1a cells with UV light induced cytoplasmic shrinkage, nuclear fragmentation, chromatin condensation, and loss of mitochondrial cytochrome c staining (Fig. 2A, panel II). Quantitation of the percentage of cells with diffuse cytochrome c fluorescence showed a marked increase in cytochrome c release following UV irradiation (Fig. 2B; P < 0.001).
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Akt prevents the release of cytochrome c induced by
multiple apoptotic stimuli.
We extended these results by testing
the ability of Akt to inhibit cytochrome c release from two
additional inducers of apoptosis, the topoisomerase inhibitor etoposide
and overexpression of Myc. Treatment of Rat1a cells with etoposide
resulted in a release of cytochrome c, as measured by loss
of punctate cytochrome c immunofluorescence (Fig.
3A; P < 0.001).
Activated Akt was sufficient to prevent the etoposide-mediated release
of cytochrome c (Fig. 3A; P < 0.001). To
study Myc-mediated apoptosis we used a conditionally active Myc allele
(MycER) that permits conditional activation of Myc activity upon
addition of the 
-estradiol analog 4-hydroxytamoxifen (4-HT). Rat1a
cells expressing MycER (Rat1a/MycER cells) and cells expressing MycER
and MyrAkt (Rat1a/MycER/MyrAkt cells) were deprived of serum in the
presence of 4-HT. Activation of Myc induced a large increase in the
percentage of cells exhibiting diffuse cytochrome c
immunostaining (Fig. 3B; P < 0.001). Activated Akt was
sufficient to prevent this translocation of cytochrome c
(Fig. 3B; P < 0.001). These data demonstrate that in
Rat1a cells, cytochrome c is released in response to a wide
range of apoptotic stimuli and that activation of Akt is sufficient to
prevent this release.
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Akt prevents alterations in mitochondrial dye uptake following UV
exposure.
Alterations in the mitochondrial inner membrane
potential (
m) have been implicated in the execution of
apoptosis (reviewed in references 15 and
23). Pharmacological studies have suggested that the
loss of inner membrane potential (
m) is due to
alterations in permeability transition (PT) pores; multiprotein
complexes located between the inner and outer membranes. Artificial
induction of PT pores opening can trigger caspase activation, and
pharmacological inhibition of PT can prevent nuclear DNA condensation
and apoptosis. In many cases, however, m collapse is
preceded by cytochrome c release and caspase activation
(4, 22, 40, 45). A recent study has presented evidence
supporting a causative role for a hyperpolarization and swelling of
mitochondria, and the subsequent cytochrome c release, in
the induction of apoptosis (40).
m low). Activated Akt delayed the appearance of
m low cells until 17 h following irradiation
(Fig. 4B). Five hours after irradiation, >45% of Rat1a cells
exhibited fragmented and condensed nuclei (Fig. 1A), while only less
than 10% of the cells had lost membrane potential. These results
strongly suggest that in our system, m low is a late
event that occurs as a consequence of apoptosis. Interestingly, we
observe an initial threefold increase in dye incorporation following
irradiation (m high), which is also significantly
attenuated by MyrAkt (Fig. 4B). Thus, Akt activation, like
Bcl-xL overexpression (40), is sufficient to
delay increases in mitochondrial dye uptake and hyperpolarization. We
obtained virtually identical results when these experiments were
repeated using the mitochondrial dye MitoTracker-CMXRos (data not
shown). The initial increase in dye uptake may reflect swelling of the mitochondria which precedes cytochrome c release. Thus, Akt
inhibits cytochrome c release by delaying the early changes
in the mitochondria immediately after the exposure to the apoptotic
stimulus.
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Akt cannot inhibit apoptosis induced by microinjection of cytochrome c. Microinjection of holo-cytochrome c can induce apoptosis in some cell lines (9, 25). We tested whether microinjection of holo-cytochrome c was able to induce cell death in Rat1a cells and whether Akt could prevent cytochrome c-induced cell death. Rat1a cells were injected with 0.1 to 10 mg of horse heart holo-cytochrome c per ml together with the dye Texas red. We observed a dose-dependent induction of apoptosis, as judged by fragmentation of nuclei beginning with 0.3 mg of cytochrome c per ml (data not shown). Because 1 mg/ml was the lowest concentration of cytochrome c that reproducibly induced apoptosis, we used this concentration for further experiments. Injection of 1 mg of cytochrome c per ml induced Rat1a cells to undergo apoptosis within 60 min of microinjection (Fig. 5; P < 0.001). Injection of 1 mg of BSA per ml did not induce any significant fragmentation of nuclei (Fig. 5B). Preincubation with zVAD was sufficient to prevent nuclear fragmentation induced by cytochrome c microinjection (Fig. 5; P < 0.001). Cells expressing MyrAkt were not protected from cytochrome c-induced cell death (Fig. 5). Taken together, these results demonstrate that although Akt can prevent cytochrome c release, it is unable to inhibit apoptosis after cytochrome c has accumulated in the cytoplasm. Therefore, the inhibition of cytochrome c release from mitochondria is a major mechanism by which Akt prevents cell death.
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Akt inhibits apoptosis induced by overexpression of the proapoptotic Bcl-2 family members. We have presented evidence that Akt prevents the disruption of mitochondrial integrity following apoptotic stimuli. As Bcl-2 family members also control mitochondrial integrity (reviewed in reference 1), it is possible that Akt functions by regulating this family of proteins. We have shown previously that Akt does not change the steady-state expression levels of the Bcl-2 and Bcl-xL proteins (20). We therefore examined the ability of Akt to inhibit apoptosis mediated by the proapoptotic members of the Bcl-2 family. Overexpression of Bax, Bak, Bik, and Bad induced a significant increase in apoptosis in Rat1a cells upon serum deprivation that was significantly attenuated by activated Akt (Fig. 6A).
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and ,
respectively. In Rat1a cells deprived of FCS, the majority of Bad
existed as the faster-migrating species (Fig. 6B, lane 1).
Treatment of the cells with FCS resulted in a shift in mobility of Bad
to the slower-migrating species (lane 2). Pretreatment of the cells
with wortmannin prevented this serum-induced mobility shift (lane 3).
In Rat1a/MyrAkt cells, Bad migrated predominantly as the species,
irrespective of the presence or absence of serum or wortmannin (lanes 5 to 7). Bad* migrated exclusively as the species irrespective of the
presence or absence of serum and/or wortmannin (lanes 7a and 8). The
presence of MyrAkt was unable to induce a mobility shift in
Bad*-expressing cells (data not shown). Thus, in Rat1a cells, Akt is
sufficient to induce a mobility shift of ectopically expressed Bad that
is dependent on S112 and S136.
We next investigated whether Bad-induced apoptosis involves cytochrome
c release and whether Akt is capable of preventing this
release. Cytochrome c release was measured in UV-treated Rat1a and Rat1a/MyrAkt cells expressing Bad or Bad*. Under these conditions, ectopic expression of Bad and Bad* increased the percentage of cells with diffuse cytochrome c immunostaining (Fig. 6C;
P < 0.002 <0.001). Akt was able to prevent release of
cytochrome c induced by Bad and to a lesser extent by Bad*
(Fig. 6C; P < 0.001). We then determined whether the
mechanism by which Akt inhibits apoptosis mediated by other
proapoptotic members of the Bcl-2 family is also through the inhibition
of cytochrome c release. Because Bak is a potent accelerator
of apoptosis in Rat1a cells, we examined the ability of Akt to inhibit
the cytochrome c release induced by overexpression of Bak,
as a representative of the Bax subfamily. Overexpression of Bak also
elicited an increase in cytochrome c release that was
significantly inhibited by Akt (Fig. 6D). These results show that Akt
inhibits apoptosis and cytochrome c release induced by both
the BH3 subfamily and the Bax subfamily of the proapoptotic Bcl-2
family. Furthermore, these results suggest that Bad is not the only
target for Akt upstream of cytochrome c release (see
discussion below).
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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In mammalian cells, the serine/threonine kinase Akt/PKB is widely recognized as the major mediator of growth factor-promoted cell survival, but the step at which it abrogates the apoptosis cascade remained unknown. A critical early step is initiated by loss of integrity of the outer mitochondrial membrane accompanied by release of cytochrome c. Cytochrome c then binds to and activates the Ced-4 homologue Apaf-I, which in turn activates caspase-9, resulting in the execution of a caspase cascade culminating in caspase-3 and caspase-7. In the present study, we demonstrated that Akt can prevent the activation and the processing of the caspases by maintaining mitochondrial integrity and by preventing the critical early step of cytochrome c release. The data for dye uptake (Fig. 4) suggest that Akt can block also the swelling of the mitochondria which preceded cytochrome c release, as was shown for Bcl-xL (40). While mitochondrial step of apoptosis is at least in part controlled by Bcl-2 family of proteins, we failed to detected changes in the levels of such proteins upon introduction of constitutively active Akt (20). One possible candidate that may mediate the regulation of mitochondrial integrity by Akt is the proapoptotic Bcl-2 family member Bad. Bad has been shown to be directly phosphorylated and inactivated by Akt. Our results are consistent with Bad being a downstream target of Akt-mediated mitochondrial integrity in cells overexpressing Bad. Although this phenomenon is important for Akt-mediated survival of cells overexpressing Bad, we have presented evidence for the existence of a more general, Bad-independent mechanism of Akt action. First, in this study we have demonstrated that Akt can overturn effects of proapoptotic Bcl-2 family members (Bik, Bak, and Bax) that lack Akt phosphorylation sites. Second, Akt showed small yet reproducible and statistically significant protection from the effects of an overexpressed Bad mutant that is insensitive to Akt phosphorylation (Fig. 6A). Moreover, Akt can completely protect from a certain threshold level of unphosphorylated Bad, because there is always a significant fraction of unphosphorylated Bad when wild-type Bad is overexpressed (Fig. 6B, lanes 4 to 6). Importantly, these phenomena were observed in Rat1a cells that lack any detectable Bad protein (19a). Third, Akt promotes survival of cells of various tissues origins and in response to diverse stimuli. Bad-deficient mice, however, lack major apoptotic defects (22a), and their primary fibroblasts are as sensitive to serum withdrawal as the wild-type cells (19a). Finally, while this report was in review, it was shown that Akt is unlikely to be the major kinase that phosphorylates Bad in vivo (18).
An alternative route of Akt action was suggested by the finding that Akt can directly phosphorylate and inactivate caspase-9 (6). The latter is expected to have an effect analogous to that of the caspase inhibitor zVAD. In contrast, our data indicate that Akt (but not zVAD) blocks release of mitochondrial cytochrome c in a caspase-independent manner (Fig. 2), while zVAD (but not Akt) attenuates cell death upon cytochrome c microinjection (Fig. 5). Noteworthy, caspase-9 deficiency interferes with apoptosis without preventing cytochrome c release (17).
Taken together, our findings demonstrate that Akt intervenes in the apoptotic pathway independently of caspases by inhibiting mitochondrial changes prior to cytochrome c release. In addition, to this mechanism that counteracts the effects of diverse apoptotic stimuli and proapoptotic proteins, there are more specific mechanisms such as phosphorylation of Bad and caspase-9 (Fig. 7). Although our results do not support Akt-mediated cell survival through inhibition of caspase-9, we cannot completely rule out the possibility that in addition to preventing cytochrome c release, Akt phosphorylates and inactivates caspase-9 and other caspases. This mechanism together with the phosphorylation of Bad could be alternative or safeguard mechanisms for Akt-mediated cell survival.
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The exact mechanism by which Akt maintains mitochondrial integrity is not clear. It is possible that Akt is antagonizing the initial damage to the mitochondria induced by the apoptotic stimuli. Because the nature and the identity of this early event are not known, it is unclear how Akt regulates the integrity of the mitochondria. However, it is likely that this mechanism is evolutionarily conserved because Akt exhibits antiapoptotic effects in both mammalian and Drosophila cells (3, 36).
The mechanism by which Akt maintains the integrity of mitochondria is likely to be similar to the effect of growth factors on mitochondria. It has been recently shown that growth factor deprivation decreases the accessibility of mitochondrial matrix to ADP, which in turn elicits hyperpolarization of the inner mitochondrial membrane and matrix swelling. Bcl-xL prevents cell death upon growth factor withdrawal by bypassing the inaccessibility of mitochondria to ADP, thereby inhibiting hyperpolarization and swelling of mitochondria (39). Because activated Akt can prevent the initial swelling and hyperpolarization of mitochondria, it is likely that it inhibits cell death by maintaining accessibility of mitochondria to ADP.
While this report was in review, another possible mechanism by which Akt promotes cell survival was suggested: Akt prevents the expression of Fas ligand upon growth factor withdrawal (5). This implies that in serum-deprived cells, the apoptotic signal is relayed to mitochondria via a caspase-8-dependent pathway which is sensitive to zVAD (26). Our observations, however, do not support this prediction because zVAD fails to prevent cytochrome c release, although it is capable of inhibiting the onset of subsequent apoptotic changes.
Both the apoptotic cascade and Akt are conserved in Caenrhabditis elegans and in Drosophila. Thus, it is expected that Akt will also have a role in regulating apoptosis in nematodes and flies. Indeed, Akt was shown in C. elegans to be a downstream effector of insulin-like growth factor receptor and PI 3-kinase (30). Thus far, there is no evidence that Akt plays a role in regulating apoptosis in C. elegans. In this regard, it is worth noting that although the fundamental apoptotic machinery is conserved between C. elegans and mammals, no role in apoptosis has been attributed to cytochrome c in C. elegans. Because Akt inhibits apoptosis by preventing cytochrome c release, it may not have a role in the regulation of apoptosis in C. elegans. Interestingly, in mammalian cells, Bcl-2 can intervene in two steps of apoptosis: it can prevent cytochrome c release and can also physically interact with Apaf-I to inhibit its function similar to the interaction between Ced-9 and Ced-4 in C. elegans (reference 1 and Fig. 7). This may explain the ability of Bcl-2, at least in some cases, to inhibit apoptosis after cytochrome c release (34). It was shown that Akt is required in Drosophila for blocking apoptosis in the embryos but has only modest effect on apoptosis in the Drosophila eye (3, 36). It remains to be seen whether Drosophila has also adopted cytochrome c as an apoptosis cofactor.
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ACKNOWLEDGMENTS |
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We thank Maura O'Leary for technical assistance, R. Dekoter and H. Singh for pBabe(eGFP), E. Eves and M. Rosner for use of the microinjection apparatus, S. Korsmeyer for communicating results before publication, and C. Palfrey for critical reading of the manuscript.
This work was supported by grants CA71874 and AG16927 from the National Institutes of Health to N.H.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Molecular Genetics (M/C 669), University of Illinois in Chicago, 900 South Ashland Ave., Chicago, IL 60607. Phone: (312) 355-1684. Fax: (312) 355-2032. E-mail: nhay{at}uic.edu.
Present address: Dept. of Molecular Biology, MGH and Harvard
Medical School, Boston, Mass.
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Top
Abstract
Introduction
Materials and Methods
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Discussion
References
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(2003). Epidermal Growth Factor Receptor-dependent, NF-{kappa}B-independent Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway Inhibits Ultraviolet Irradiation-induced Caspases-3, -8, and -9 in Human Keratinocytes. J. Biol. Chem.
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Headrick, J. P., Hack, B., Ashton, K. J.
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285: H1797-H1818
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Zazzeroni, F., Papa, S., Algeciras-Schimnich, A., Alvarez, K., Melis, T., Bubici, C., Majewski, N., Hay, N., De Smaele, E., Peter, M. E., Franzoso, G.
(2003). Gadd45{beta} mediates the protective effects of CD40 costimulation against Fas-induced apoptosis. Blood
102: 3270-3279
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Liao, Y., Hung, M.-C.
(2003). Regulation of the Activity of p38 Mitogen-Activated Protein Kinase by Akt in Cancer and Adenoviral Protein E1A-Mediated Sensitization to Apoptosis. Mol. Cell. Biol.
23: 6836-6848
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Kang, J.-Q., Chong, Z. Z., Maiese, K.
(2003). Critical Role for Akt1 in the Modulation of Apoptotic Phosphatidylserine Exposure and Microglial Activation. Mol. Pharmacol.
64: 557-569
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Ouyang, T., Bai, R.-Y., Bassermann, F., von Klitzing, C., Klumpen, S., Miething, C., Morris, S. W., Peschel, C., Duyster, J.
(2003). Identification and Characterization of a Nuclear Interacting Partner of Anaplastic Lymphoma Kinase (NIPA). J. Biol. Chem.
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Doonan, F., Donovan, M., Cotter, T. G.
(2003). Caspase-Independent Photoreceptor Apoptosis in Mouse Models of Retinal Degeneration. J. Neurosci.
23: 5723-5731
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Woo, J.-H., Kim, Y.-H., Choi, Y.-J., Kim, D.-G., Lee, K.-S., Bae, J. H., Min, D. S., Chang, J.-S., Jeong, Y.-J., Lee, Y. H., Park, J.-W., Kwon, T. K.
(2003). Molecular mechanisms of curcumin-induced cytotoxicity: induction of apoptosis through generation of reactive oxygen species, down-regulation of Bcl-XL and IAP, the release of cytochrome c and inhibition of Akt. Carcinogenesis
24: 1199-1208
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HA, K.-S., KIM, K.-M., KWON, Y.-G., BAI, S.-K., NAM, W.-D., YOO, Y.-M., KIM, P. K. M., CHUNG, H.-T., BILLIAR, T. R., KIM, Y.-M.
(2003). Nitric oxide prevents 6-hydroxydopamine-induced apoptosis in PC12 cells through cGMP-dependent PI3 kinase/Akt activation. FASEB J.
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Schwertfeger, K. L., McManaman, J. L., Palmer, C. A., Neville, M. C., Anderson, S. M.
(2003). Expression of constitutively activated Akt in the mammary gland leads to excess lipid synthesis during pregnancy and lactation. J. Lipid Res.
44: 1100-1112
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Shimamura, H., Terada, Y., Okado, T., Tanaka, H., Inoshita, S., Sasaki, S.
(2003). The PI3-Kinase-Akt Pathway Promotes Mesangial Cell Survival and Inhibits Apoptosis In Vitro via NF-{kappa}B and Bad. J. Am. Soc. Nephrol.
14: 1427-1434
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Won, J., Kim, D. Y., La, M., Kim, D., Meadows, G. G., Joe, C. O.
(2003). Cleavage of 14-3-3 Protein by Caspase-3 Facilitates Bad Interaction with Bcl-x(L) during Apoptosis. J. Biol. Chem.
278: 19347-19351
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UMEDA, J., SANO, S., KOGAWA, K., MOTOYAMA, N., YOSHIKAWA, K., ITAMI, S., KONDOH, G., WATANABE, T., TAKEDA, J.
(2003). In vivo cooperation between Bcl-xL and the phosphoinositide 3-kinase-Akt signaling pathway for the protection of epidermal keratinocytes from apoptosis. FASEB J.
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Znamensky, V., Akama, K. T., McEwen, B. S., Milner, T. A.
(2003). Estrogen Levels Regulate the Subcellular Distribution of Phosphorylated Akt in Hippocampal CA1 Dendrites. J. Neurosci.
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Roux, P. P., Dorval, G., Boudreau, M., Angers-Loustau, A., Morris, S. J., Makkerh, J., Barker, P. A.
(2002). K252a and CEP1347 Are Neuroprotective Compounds That Inhibit Mixed-lineage Kinase-3 and Induce Activation of Akt and ERK. J. Biol. Chem.
277: 49473-49480
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Chong, Z. Z., Kang, J.-Q., Maiese, K.
(2002). Erythropoietin Is a Novel Vascular Protectant Through Activation of Akt1 and Mitochondrial Modulation of Cysteine Proteases. Circulation
106: 2973-2979
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Ferry, S., Matsuda, M., Yoshida, H., Hirata, M.
(2002). Inositol hexakisphosphate blocks tumor cell growth by activating apoptotic machinery as well as by inhibiting the Akt/NF{kappa}B-mediated cell survival pathway. Carcinogenesis
23: 2031-2041
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Linseman, D. A., Phelps, R. A., Bouchard, R. J., Le, S. S., Laessig, T. A., McClure, M. L., Heidenreich, K. A.
(2002). Insulin-Like Growth Factor-I Blocks Bcl-2 Interacting Mediator of Cell Death (Bim) Induction and Intrinsic Death Signaling in Cerebellar Granule Neurons. J. Neurosci.
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van den Heuvel, A. P. J., de Vries-Smits, A. M. M., van Weeren, P. C., Dijkers, P. F., de Bruyn, K. M. T., Riedl, J. A., Burgering, B. M. T.
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Maddock, H. L., Mocanu, M. M., Yellon, D. M.
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283: H1307-H1313
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Schulman, D., Latchman, D. S., Yellon, D. M.
(2002). Urocortin protects the heart from reperfusion injury via upregulation of p42/p44 MAPK signaling pathway. Am. J. Physiol. Heart Circ. Physiol.
283: H1481-H1488
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Kandasamy, K., Srivastava, R. K.
(2002). Role of the Phosphatidylinositol 3'-Kinase/PTEN/Akt Kinase Pathway in Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Non-Small Cell Lung Cancer Cells. Cancer Res.
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Webster, C. R. L., Usechak, P., Anwer, M. S.
(2002). cAMP inhibits bile acid-induced apoptosis by blocking caspase activation and cytochrome c release. Am. J. Physiol. Gastrointest. Liver Physiol.
283: G727-G738
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Edwards, E., Geng, L., Tan, J., Onishko, H., Donnelly, E., Hallahan, D. E.
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Seubert, J. M., Darmon, A. J., El-Kadi, A. O. S., D'Souza, S. J. A., Bend, J. R.
(2002). Apoptosis in Murine Hepatoma Hepa 1c1c7 Wild-Type, C12, and C4 Cells Mediated by Bilirubin. Mol. Pharmacol.
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Clark, A. S., West, K., Streicher, S., Dennis, P. A.
(2002). Constitutive and Inducible Akt Activity Promotes Resistance to Chemotherapy, Trastuzumab, or Tamoxifen in Breast Cancer Cells. Molecular Cancer Therapeutics
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Ogawara, Y., Kishishita, S., Obata, T., Isazawa, Y., Suzuki, T., Tanaka, K., Masuyama, N., Gotoh, Y.
(2002). Akt Enhances Mdm2-mediated Ubiquitination and Degradation of p53. J. Biol. Chem.
277: 21843-21850
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Lee, H.-Y., Chun, K.-H., Liu, B., Wiehle, S. A., Cristiano, R. J., Hong, W. K., Cohen, P., Kurie, J. M.
(2002). Insulin-like Growth Factor Binding Protein-3 Inhibits the Growth of Non-Small Cell Lung Cancer. Cancer Res.
62: 3530-3537
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ten Berge, R. L., Meijer, C. J. L. M., Dukers, D. F., Kummer, J. A., Bladergroen, B. A., Vos, W., Hack, C. E., Ossenkoppele, G. J., Oudejans, J. J.
(2002). Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma. Blood
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Budinger, G. R. S., Tso, M., McClintock, D. S., Dean, D. A., Sznajder, J. I., Chandel, N. S.
(2002). Hyperoxia-induced Apoptosis Does Not Require Mitochondrial Reactive Oxygen Species and Is Regulated by Bcl-2 Proteins. J. Biol. Chem.
277: 15654-15660
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Karpinich, N. O., Tafani, M., Rothman, R. J., Russo, M. A., Farber, J. L.
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277: 16547-16552
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Tsuruta, F., Masuyama, N., Gotoh, Y.
(2002). The Phosphatidylinositol 3-Kinase (PI3K)-Akt Pathway Suppresses Bax Translocation to Mitochondria. J. Biol. Chem.
277: 14040-14047
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Gabai, V. L., Sherman, M. Y.
(2002). Molecular Biology of Thermoregulation: Invited Review: Interplay between molecular chaperones and signaling pathways in survival of heat shock. J. Appl. Physiol.
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Sears, R. C., Nevins, J. R.
(2002). Signaling Networks That Link Cell Proliferation and Cell Fate. J. Biol. Chem.
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Kunstle, G., Laine, J., Pierron, G., Kagami, S.-i., Nakajima, H., Hoh, F., Roumestand, C., Stern, M.-H., Noguchi, M.
(2002). Identification of Akt Association and Oligomerization Domains of the Akt Kinase Coactivator TCL1. Mol. Cell. Biol.
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Wobser, H., Du{beta}mann, H., Kogel, D., Wang, H., Reimertz, C., Wollheim, C. B., Byrne, M. M., Prehn, J. H. M.
(2002). Dominant-negative Suppression of HNF-1alpha Results in Mitochondrial Dysfunction, INS-1 Cell Apoptosis, and Increased Sensitivity to Ceramide-, but Not to High Glucose-induced Cell Death. J. Biol. Chem.
277: 6413-6421
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Dijkers, P. F., Birkenkamp, K. U., Lam, E. W.-F., Thomas, N. S. B., Lammers, J.-W. J., Koenderman, L., Coffer, P. J.
(2002). FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B-enhanced cell survival through maintenance of mitochondrial integrity. JCB
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Bae, Y.-S., Kim, Y., Park, J. C., Suh, P.-G., Ryu, S. H.
(2002). The synthetic chemoattractant peptide, Trp-Lys-Tyr-Met-Val-D-Met, enhances monocyte survival via PKC-dependent Akt activation. J. Leukoc. Biol.
71: 329-338
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Hu, L., Hofmann, J., Lu, Y., Mills, G. B., Jaffe, R. B.
(2002). Inhibition of Phosphatidylinositol 3'-Kinase Increases Efficacy of Paclitaxel in in Vitro and in Vivo Ovarian Cancer Models. Cancer Res.
62: 1087-1092
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Pap, M., Cooper, G. M.
(2002). Role of Translation Initiation Factor 2B in Control of Cell Survival by the Phosphatidylinositol 3-Kinase/Akt/Glycogen Synthase Kinase 3{beta} Signaling Pathway. Mol. Cell. Biol.
22: 578-586
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McClintock, D. S., Santore, M. T., Lee, V. Y., Brunelle, J., Budinger, G. R. S., Zong, W.-X., Thompson, C. B., Hay, N., Chandel, N. S.
(2002). Bcl-2 Family Members and Functional Electron Transport Chain Regulate Oxygen Deprivation-Induced Cell Death. Mol. Cell. Biol.
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Carson, J. P., Behnam, M., Sutton, J. N., Du, C., Wang, X., Hunt, D. F., Weber, M. J., Kulik, G.
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Su, F., Overholtzer, M., Besser, D., Levine, A. J.
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Abreu, M. T., Arnold, E. T., Chow, J. Y. C., Barrett, K. E.
(2001). Phosphatidylinositol 3-Kinase-dependent Pathways Oppose Fas-induced Apoptosis and Limit Chloride Secretion in Human Intestinal Epithelial Cells. IMPLICATIONS FOR INFLAMMATORY DIARRHEAL STATES. J. Biol. Chem.
276: 47563-47574
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Yum, H.-K., Arcaroli, J., Kupfner, J., Shenkar, R., Penninger, J. M., Sasaki, T., Yang, K.-Y., Park, J. S., Abraham, E.
(2001). Involvement of Phosphoinositide 3-Kinases in Neutrophil Activation and the Development of Acute Lung Injury. J. Immunol.
167: 6601-6608
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DORSCHEID, D. R., WOJCIK, K. R., SUN, S., MARROQUIN, B., WHITE, S. R.
(2001). Apoptosis of Airway Epithelial Cells Induced by Corticosteroids. Am. J. Respir. Crit. Care Med.
164: 1939-1947
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Prejean, C., Sarma, T., Kurnasov, O., Usacheva, A., Hemmings, B., Cantley, L., Fruman, D. A., Morrison, L. A., Buller, R. M., Colamonici, O. R.
(2001). Phosphatidylinositol 3-Kinase Confers Resistance to Encephalomyocarditis and Herpes Simplex Virus-Induced Cell Death Through the Activation of Distinct Downstream Effectors. J. Immunol.
167: 4553-4559
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Thakkar, H., Chen, X., Tyan, F., Gim, S., Robinson, H., Lee, C., Pandey, S. K., Nwokorie, C., Onwudiwe, N., Srivastava, R. K.
(2001). Pro-survival Function of Akt/Protein Kinase B in Prostate Cancer Cells. RELATIONSHIP WITH TRAIL RESISTANCE. J. Biol. Chem.
276: 38361-38369
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Tureckova, J., Wilson, E. M., Cappalonga, J. L., Rotwein, P.
(2001). Insulin-like Growth Factor-mediated Muscle Differentiation. COLLABORATION BETWEEN PHOSPHATIDYLINOSITOL 3-KINASE-Akt-SIGNALING PATHWAYS AND MYOGENIN. J. Biol. Chem.
276: 39264-39270
[Abstract] [Full Text]
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